肿瘤突变负荷

什么是肿瘤突变负荷（TMB）？

肿瘤突变负荷（TMB）是指肿瘤基因组编码区内体细胞突变的数量。它与对免疫治疗药物（如检查点抑制剂）的反应相关^1-5。研究表明，高肿瘤突变负荷会增加肿瘤细胞表达的免疫原性新抗原诱导对免疫疗法应答的可能性^1-4。

哪些类型的癌症与TMB有关？

大量临床研究表明，对于接受检查点抑制剂治疗的黑色素瘤、结肠癌和非小细胞肺癌（NSCLC）等癌症患者，突变负荷越高，患者生存率越高。过往临床试验（如CheckMate 227）的数据表明，在NSCLC中，较高的TMB与临床结果改善相关⁶。

TMB的概率

在各种肿瘤类型中，13%-26%的晚期癌症患者表现出高TMB^5,7-10。

使用NGS进行TMB检测

为了准确评估TMB，需要使用约1.1 Mb编码基因组进行大型检测^{11, 12}。全景变异分析（CGP）可同时分析数百种生物标志物，包括TMB。

利用CGP改善高TMB的精准医疗

当在mNSCLC中检测到1 Mb≥20个突变时，使用CGP从血液中测得的TMB（bTMB）与改善临床结果相关^13-15。

TMB的免疫治疗

临床试验和监管批准已经为多种肿瘤类型建立了多种免疫疗法¹⁶。识别分子特征的能力有助于预测对这些治疗的响应，这对于更好地预测哪些患者将从这些治疗中受益至关重要。

肿瘤突变负荷（TMB）和微卫星不稳定性（MSI）状态是FDA批准的两种指示患者对免疫疗法响应情况的生物标志物，并且指南建议检测这两种生物标志物^17-18。

针对高TMB癌症的获批疗法

了解美国FDA批准的高TMB癌症疗法的最新情况。

查看FDA批准情况

使用全景变异分析方法进行TMB NGS检测

全景变异分析（CGP）可以在核苷酸水平检测生物标志物，通常包括所有大型基因组特征（TMB、MSI），大幅提升了检测具有临床意义的突变的能力。

单基因和小型热点panel检测方法在检测已知和新型生物标志物和分子特征方面的能力有限，可能会漏检重要的目标变异^19-22。CGP提供了广泛的基因组分子覆盖，在一次检测中即可捕获一组全面的临床相关基因。

通过单次NGS检测评估肿瘤类型

全景变异分析（CGP）可以提供有意义的结果和可能有意义的结果，帮助癌症患者确定更有效的治疗途径，提供创新的临床试验选择。

深入了解CGP

TMB工作流程

文库制备

TruSight Oncology Comprehensive IVD

TruSight Oncology Comprehensive（EU）是因美纳首个获CE认证的体外诊断试剂盒，用于基于DNA和RNA的全景变异分析，将多次重复检测整合为一次检测。

测序

NextSeq 550Dx测序仪

NextSeq 550Dx测序仪是一款获得CE认证的IVD仪器，使临床实验室能够开发并开展各种应用。

数据分析

Local Run Manager TruSight Oncology Comprehensive（EU）分析模块（机载软件）

使用TruSight Oncology Comprehensive Local Run Manager分析模块分析结果。

参考文献

Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348 (6230):124-128.
Snyder A, Makarov V, Merghoub T, et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. N Engl J Med. 2014;371(23):2189-2199.
Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207-211.
Garofalo A, Sholl L, Reardon B, et al. The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med. 2016;8(1):79. doi:10.1186/s13073-016-0333-9.
Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi.org/10.1016/S1470-2045(20)30445-9.
Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378(22): 2093–2104.
European Society for Medical Oncology. Guidelines | ESMO. ESMO website. https://www.esmo.org/guidelines. Accessed February 10, 2021. 16.
Cristescu, R, Aurora-Garg, D, Albright, D, et al. Association Between Tumor Mutational Burden Assessed by Whole-Exome Sequencing and Outcomes of Pembrolizumab Monotherapy. Poster presented at: 2020 American Association of Cancer Research Virtual Annual Meeting II; June 22-24, 2020. LB-261.
Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202-206. doi:10.1038/s41588-018-0312-8.
Goodman AM, Kato S, Bazhenova L, et al. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther. 2017;16(11):2598-2608. doi:10.1158/1535-7163.MCT-17-0386.
Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. Published 2017 Apr 19. doi:10.1186/s13073-017-0424-2.
Buchhalter I, Rempel E, Endris V, et al. Size matters: Dissecting key parameters for panel-based tumor mutational burden analysis. Int J Cancer. 2019;144(4):848-858. doi:10.1002/ijc.31878.
Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in Firstline Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):661-674. doi:10.1001/jamaoncol.2020.0237.
Garassino MC, Gadgeel SM, Rodriguez-Abreu D, et al. Evaluation of blood TMB (bTMB) in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) with pemetrexed and platinum versus placebo plus chemo as first-line therapy for metastatic nonsquamous NSCLC. J Clin Oncol. 2020;38:15_suppl, 9521-9521. doi: 10.1158/1078-0432.CCR-20-3771.
Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448. doi:10.1038/s41591-018-0134-3.
Emens LA, Ascierto PA, Darcy PK, et al. Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017;81:116-129. doi:10.1016/j.ejca.2017.01.035
Luchini C, Bibeau F, Ligtenberg MJ, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann. Oncol. 2019;30(8):1232-1243. doi:https://doi.org/10.1093/annonc/mdz116.
Chakravarty D, Johnson A, Sklar J, et al. Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion. J. Clin. 2022; 40(11):1231-1258. doi: 10.1200/JCO.21.02767.
Suh JH, Johnson A, Albacker L, et al. Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials. Oncologist. 2016;21(6):684-691. doi:10.1634/theoncologist.2016-0030.
Drilon A, Wang L, Arcila ME, et al. Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches. Clin Cancer Res. 2015;21(16):3631-3639. doi:10.1158/1078-0432.CCR-14-2683.
Ali SM, Hensing T, Schrock AB, et al. Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALKRearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization. Oncologist. 2016;21(6):762-770. doi:10.1634/theoncologist.2015-0497.
Schrock AB, Frampton GM, Herndon D, et al. Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing. Clin Cancer Res. 2016;22(13):3281-3285. doi:10.1158/1078-0432. CCR-15-1668.

肿瘤突变负荷检测